Lighting the chandelier: new vistas for axo-axonic cells

doi:10.1016/j.tins.2005.04.004

Trends in Neurosciences

Volume 28, Issue 6, June 2005, Pages 310-316

https://doi.org/10.1016/j.tins.2005.04.004 Get rights and content

Chandelier or axo-axonic cells are the most selective of all cortical GABAergic interneurons, because they exclusively contact axon initial segments of cortical glutamatergic neurons. Owing to their privileged location on initial segments, axo-axonic cells have often been assumed to have the ultimate control of pyramidal cell output. Recently, key molecules expressed at the initial-segment synapses have been identified, and novel in vitro and in vivo electrophysiological studies have revealed unexpectedly versatile functional effects exerted by axo-axonic cells on their postsynaptic targets. In addition, there is also emerging recognition of the mechanistic involvement of these unique cells in several neurological diseases, including epilepsy and schizophrenia.

Introduction

In his pioneering studies of neuroanatomy, Santiago Ramon y Cajal identified many major interneuron subtypes, yet never explicitly described the characteristic cartridges of axo-axonic cells (AACs). Chandelier cells, so named by János Szentágothai because these cartridges (vertical rows of axonal terminals) resemble rows of candles on a chandelier (Figure 1a,b), were discovered only 30 years ago 1, 2. Shortly thereafter, in Golgi-stained tissue from rat cortex, it was recognized that chandelier cells are the source of the previously mysterious axo-axonic boutons [3] and are not dendritically projecting, as previously believed. A few years later, the GABAergic, and therefore inhibitory, nature of these cells was verified [4]. This short but distinguished heritage gave rise to a series of recent breakthroughs that underlie the unique nature of these elusive interneurons.

Section snippets

Location and basic properties

Curiously, nearly all AACs are located in layered cortical areas – the neocortex or allocortex 3, 5, 6, 7. However, AAC cartridges have also been found throughout the amygdala, a partly cortical structure that is not laminated [8], and AACs do not exist in the cerebellar cortex, despite its layered nature. Because the home of AACs, the cerebral cortex, is evolutionarily recent, it is perhaps no coincidence that AACs have been identified so far only in mammals, including rats [3], guinea pigs [9]

Identification, please: markers for AACs

As the field of interneuron diversity developed, biochemical markers were discovered as distinguishing characteristics. The first marker found for AACs was the Ca²⁺-binding protein parvalbumin (PV), expressed in nearly every AAC 5, 20. Unfortunately, PV is not specific to AACs – it is also expressed by some basket cells. AAC cartridges are reliably stained by the high-affinity GABA transporter GAT-1, but identification relies on the presence of characteristic cartridges because GAT-1 labels

Picking partners: postsynaptic targets of AACs

Although other cell types show target specificity, AACs outshine them all with their remarkable precision. In nearly all quantitative studies, regardless of species or brain area, every chandelier cell terminal synapses with the AISs of pyramidal cells, granule cells or mossy cells 3, 7, 10, 14, 16, 28, 29, 30. In the few studies that could not confirm total specificity, the percentage of synapses onto AISs was never <90% 31, 32, 33. It could be important that these AACs with aberrant targets

Sixteen candles: development of a chandelier

Studying development of specific interneuron subtypes is not trivial because identification relies on Ca²⁺-binding-protein expression and neurite arborization patterns, which often appear relatively late in development. A study in monkeys of AAC cartridges, visualized using Golgi staining, PV-immunoreactivity or GAT-1-immunoreactivity, indicated a biphasic developmental course, increasing from a few stained cartridges at birth to a maximum during adolescence, and then possibly decreasing again

The other side of the synapse: molecular layout of the AIS

The AAC cannot be studied without considering its target the AIS, and the anatomy of the AIS elucidates its function. This axonal structure is precisely defined and exhibits unique structural features on electron micrographs, including microtubule clusters, a membrane undercoating, clusters of ribosomes, and stacks of Ca²⁺-storing cisternae 40, 41. The neuronal cytoskeleton, consisting of interacting spectrins and actins, forms the neuronal structural scaffold and is a spatial delimiter for

Chandelier cell function: more than simply inhibitory

Recently, great strides have been made in understanding physiological roles of AACs. Neocortical and hippocampal AACs, identified by electron microscopy as shown in Figure 3(a), display fast-spiking characteristics and various degrees of spike frequency accommodation, with the decrement in firing rate varying between 2.5% and 81.0% in response to a 500 ms depolarization 13, 17, 28, 30, 33, 53, 54, 55 (Figure 3b). As expected, firing of AACs evokes inhibitory postsynaptic events in pyramidal

Chandelier cells in disease states

Given the specificity and functional roles of AACs, a disturbance of these cells would be expected to cause major problems for normal function. In fact, changes in AACs have been reported in both epilepsy and schizophrenia. Many studies of both diseases have shown various amounts of decreased PV-immunoreactivity or mRNA expression 64, 65, 66, 67, 68, but this measure is not specific for AACs, nor does it necessarily signal cell death of PV-positive cells. However, some specific changes suggest

Future directions

A wealth of recent information about anatomy and physiology of AACs and the AIS indicates that these associated structures play an important part in cortical network activity. However, more work is needed to understand fully the role of AACs. For example, synaptic innervation of the pyramidal cell AIS needs to be studied using electron microscopy over the course of postnatal development, and in both control and schizophrenic tissues, to verify changes seen in protein expression studies. Given

Acknowledgements

This work was supported by the NIH (grant NS38580 to I.S.).

References (75)

P. Somogyi
A specific ‘axo-axonal’ interneuron in the visual cortex of the rat
Brain Res.
(1977)
T. Kosaka
Axon initial segments of the granule cell in the rat dentate gyrus: synaptic contacts on bundles of axon initial segments
Brain Res.
(1983)
E. Soriano et al.
A GABAergic axo-axonic cell in the fascia dentata controls the main excitatory hippocampal pathway
Brain Res.
(1989)
P. Somogyi
The axo-axonic interneuron in the cerebral cortex of the rat, cat and monkey
Neuroscience
(1982)
P. Somogyi
A new type of specific interneuron in the monkey hippocampus forming synapses exclusively with the axon initial segments of pyramidal cells
Brain Res.
(1983)
Z.F. Kisvarday
Synaptic connections of axo-axonic (chandelier) cells in human epileptic temporal cortex
Neuroscience
(1986)
M.R. del Rio et al.
Colocalization of parvalbumin and calbindin D-28k in neurons including chandelier cells of the human temporal neocortex
J. Chem. Neuroanat.
(1997)
Y. Kawaguchi et al.
Neurochemical features and synaptic connections of large physiologically-identified GABAergic cells in the rat frontal cortex
Neuroscience
(1998)
F. Ango
Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment
Cell
(2004)
G. Stuart
Action potential initiation and backpropagation in neurons of the mammalian CNS
Trends Neurosci.
(1997)

Z.F. Mainen

A model of spike initiation in neocortical pyramidal neurons

Neuron

(1995)

C.L. Beasley

Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins

Biol. Psychiatry

(2002)

P. Marco

Loss of inhibitory synapses on the soma and axon initial segment of pyramidal cells in human epileptic peritumoural neocortex: implications for epilepsy

Brain Res. Bull.

(1997)

I. Ferrer

Parvalbumin and calbindin-D28k immunocytochemistry in human neocortical epileptic foci

J. Neurol. Sci.

(1994)

C.E. Ribak

Axon terminals of GABAergic chandelier cells are lost at epileptic foci

Brain Res.

(1985)

L. Wittner

Preservation of perisomatic inhibitory input of granule cells in the epileptic human dentate gyrus

Neuroscience

(2001)

J. Szentagothai et al.

Conceptual models of neural organization

Neurosci. Res. Program Bull.

(1974)

E.G. Jones

Varieties and distribution of non-pyramidal cells in the somatic sensory cortex of the squirrel monkey

J. Comp. Neurol.

(1975)

P. Somogyi

Glutamate decarboxylase immunoreactivity in the hippocampus of the cat: distribution of immunoreactive synaptic terminals with special reference to the axon initial segment of pyramidal neurons

J. Neurosci.

(1983)

S. Schmidt

Parvalbumin-immunoreactive structures of the adult human entorhinal and transentorhinal region

Hippocampus

(1993)

S. Kemppainen et al.

Distribution of parvalbumin, calretinin, and calbindin-D(28k) immunoreactivity in the rat amygdaloid complex and colocalization with gamma-aminobutyric acid

J. Comp. Neurol.

(2000)

A.I. Gulyas

Precision and variability in postsynaptic target selection of inhibitory cells in the hippocampal CA3 region

Eur. J. Neurosci.

(1993)

A. Fairen et al.

A specialized type of neuron in the visual cortex of cat: a Golgi and electron microscope study of chandelier cells

J. Comp. Neurol.

(1980)

I.B. Muller-Paschinger

Chandelier neurons within the rabbits' cerebral cortex. A Golgi study

Anat. Embryol. (Berl.)

(1983)

C.S. Chiu

Number, density, and surface/cytoplasmic distribution of GABA transporters at presynaptic structures of knock-in mice carrying GABA transporter subtype 1-green fluorescent protein fusions

J. Neurosci.

(2002)

L.S. Krimer et al.

Prefrontal microcircuits: membrane properties and excitatory input of local, medium, and wide arbor interneurons

J. Neurosci.

(2001)

P. Ganter

Properties of horizontal axo-axonic cells in stratum oriens of the hippocampal CA1 area of rats in vitro

Hippocampus

(2004)

A. Peters

Chandelier cells in rat visual cortex

J. Comp. Neurol.

(1982)

X.G. Li

Axonal and dendritic arborization of an intracellularly labeled chandelier cell in the CA1 region of rat hippocampus

Exp. Brain Res.

(1992)

J. DeFelipe

Visualization of chandelier cell axons by parvalbumin immunoreactivity in monkey cerebral cortex

Proc. Natl. Acad. Sci. U. S. A.

(1989)

J. DeFelipe et al.

Chandelier cell axons are immunoreactive for GAT-1 in the human neocortex

NeuroReport

(1998)

I. Aradi et al.

Modulation of network behaviour by changes in variance in interneuronal properties

J. Physiol.

(2002)

D.A. Lewis et al.

Heterogeneity of chandelier neurons in monkey neocortex: corticotropin-releasing factor- and parvalbumin-immunoreactive populations

J. Comp. Neurol.

(1990)

D.A. Lewis

Corticotropin-releasing factor immunoreactivity in monkey neocortex: an immunohistochemical analysis

J. Comp. Neurol.

(1989)

J.I. Arellano

PSA-NCAM immunoreactivity in chandelier cell axon terminals of the human temporal cortex

Cereb. Cortex

(2002)

J.I. Arellano

Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus

Brain

(2004)

E.H. Buhl

Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus

J. Neurophysiol.

(1994)

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Trends in Neurosciences

INMED/TINS special issueLighting the chandelier: new vistas for axo-axonic cells

Introduction

Section snippets

Location and basic properties

Identification, please: markers for AACs

Picking partners: postsynaptic targets of AACs

Sixteen candles: development of a chandelier

The other side of the synapse: molecular layout of the AIS

Chandelier cell function: more than simply inhibitory

Chandelier cells in disease states

Future directions

Acknowledgements

Brain Res.

Brain Res.

Brain Res.

Neuroscience

Brain Res.

Neuroscience

J. Chem. Neuroanat.

Neuroscience

Cell

Trends Neurosci.

Neuron

Biol. Psychiatry

Brain Res. Bull.

J. Neurol. Sci.

Brain Res.

Neuroscience

Conceptual models of neural organization

Neurosci. Res. Program Bull.

Varieties and distribution of non-pyramidal cells in the somatic sensory cortex of the squirrel monkey

J. Comp. Neurol.

Glutamate decarboxylase immunoreactivity in the hippocampus of the cat: distribution of immunoreactive synaptic terminals with special reference to the axon initial segment of pyramidal neurons

J. Neurosci.

Parvalbumin-immunoreactive structures of the adult human entorhinal and transentorhinal region

Hippocampus

Distribution of parvalbumin, calretinin, and calbindin-D(28k) immunoreactivity in the rat amygdaloid complex and colocalization with gamma-aminobutyric acid

J. Comp. Neurol.

Precision and variability in postsynaptic target selection of inhibitory cells in the hippocampal CA3 region

Eur. J. Neurosci.

A specialized type of neuron in the visual cortex of cat: a Golgi and electron microscope study of chandelier cells

J. Comp. Neurol.

Chandelier neurons within the rabbits' cerebral cortex. A Golgi study

Anat. Embryol. (Berl.)

Number, density, and surface/cytoplasmic distribution of GABA transporters at presynaptic structures of knock-in mice carrying GABA transporter subtype 1-green fluorescent protein fusions

J. Neurosci.

Prefrontal microcircuits: membrane properties and excitatory input of local, medium, and wide arbor interneurons

J. Neurosci.

Properties of horizontal axo-axonic cells in stratum oriens of the hippocampal CA1 area of rats in vitro

Hippocampus

Chandelier cells in rat visual cortex

J. Comp. Neurol.

Axonal and dendritic arborization of an intracellularly labeled chandelier cell in the CA1 region of rat hippocampus

Exp. Brain Res.

Visualization of chandelier cell axons by parvalbumin immunoreactivity in monkey cerebral cortex

Proc. Natl. Acad. Sci. U. S. A.

Chandelier cell axons are immunoreactive for GAT-1 in the human neocortex

NeuroReport

Modulation of network behaviour by changes in variance in interneuronal properties

J. Physiol.

Heterogeneity of chandelier neurons in monkey neocortex: corticotropin-releasing factor- and parvalbumin-immunoreactive populations

J. Comp. Neurol.

Corticotropin-releasing factor immunoreactivity in monkey neocortex: an immunohistochemical analysis

J. Comp. Neurol.

PSA-NCAM immunoreactivity in chandelier cell axon terminals of the human temporal cortex

Cereb. Cortex

Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus

Brain

Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus

J. Neurophysiol.

INMED/TINS special issue
Lighting the chandelier: new vistas for axo-axonic cells